Farnesylthiosalicylic Acid-Loaded Albumin Nanoparticle Alleviates Renal Fibrosis by Inhibiting Ras/Raf1/p38 Signaling Pathway

Abstract

Background Renal fibrosis is the common pathway in chronic kidney diseases progression to end-stage renal disease, but to date, no clinical drug for its treatment is approved. It has been demonstrated that the inhibitor of proto-oncogene Ras, farnesylthiosalicylic acid (FTS), shows therapeutic potential for renal fibrosis, but its application was hindered by the water-insolubility and low bioavailability. Hence, in this study, we improved these properties of FTS by encapsulating it into bovine serum albumin nanoparticles (AN-FTS) and tested its therapeutic effect in renal fibrosis. Methods AN-FTS was developed using a classic emulsification-solvent ultrasonication. The pharmacokinetics of DiD-loaded albumin nanoparticle were investigated in SD rats. The biodistribution and therapeutic efficacy of AN-FTS was assessed in a mouse model of renal fibrosis induced by unilateral ureteral obstruction (UUO). Results AN-FTS showed a uniform spherical shape with the size of 100.6 ± 1.12 nm and PDI < 0.25. In vitro, AN-FTS displayed stronger inhibitory effects on the activation of renal fibroblasts cells NRK-49F than free FTS. In vivo, AN-FTS showed significantly higher peak concentration and area under the concentration-time curve. After intravenous administration to UUO-induced renal fibrosis mice, AN-FTS accumulated preferentially in the fibrotic kidney, and alleviated renal fibrosis and inflammation significantly more than the free drug. Mechanistically, the improved anti-fibrosis effect of AN-FTS was associated with greater inhibition in renal epithelial-to-mesenchymal transformation process via Ras/Raf1/p38 signaling pathway. Conclusion The study reveals that AN-FTS is capable of delivering FTS to fibrotic kidney and showed superior therapeutic efficacy for renal fibrosis.

A sub-10-nm, folic acid-conjugated gold nanoparticle as self-therapeutic treatment of tubulointerstitial fibrosis

“…Chitosan NPs complexed with siRNA against an inflammatory enzyme required injection 3 d prior to UUO surgery ( 9 ). Albumin NPs loaded with small molecules that block p38 signaling entailed injection 2 d post-UUO surgery ( 63 ). This point is of clinical importance; as early development of CKD is asymptomatic, patients are mostly diagnosed at a later disease stage.…”

A Cyclopentanone Compound Attenuates the Over-Accumulation of Extracellular Matrix and Fibrosis in Diabetic Nephropathy via Downregulating the TGF-β/p38MAPK Axis

“…Recently, many studies have reported that inhibiting the p38MAPK signaling pathway is beneficial to alleviate various kidney diseases [ 12 , 13 , 44 , 45 , 46 ]. Studies conducted on kidneys from hyperglycemic mice and HG-stimulated podocytes have shown that p38MAPK is involved in triggering chain reactions associated with hyperglycemia-induced nephrin endocytosis [ 47 ].…”

Application of nanoparticles in the diagnosis and treatment of chronic kidney disease

“…Huang et al encapsulated FTS in bovine serum albumin nanoparticles (AN-FTS) to improve its characteristics. Mouse experiments have demonstrated that AN-FTS preferentially accumulates in the fibrotic kidney, which can significantly reduce renal fibrosis and inflammation compared to free drugs ( 43 ).…”